The overall goal of this project is to test the hypothesis that acromegaly is a disorder of a hypothalamic origin resulting from an augmented secretion of hypothalamic growth hormone- releasing factor (GRF). This hypothesis will be approached in several ways. Specifically, we plan: 1) To perform a detailed analysis of the pulsatile pattern of growth hormone secretion and to assess pituitary sensitivity to GRF in patients with acromegaly; 2) To study effects of pulsatile GRF administration upon GH secretion in normal controls and in patients with isolated GH deficiency (IGHD); 3) To explore the possibility that the feedback inhibition of growth hormone secretion by somatomedin C is defective in patients with acromegaly; 4) To assess the integrity of endogenous hypothalamic somatostatin secretion in acromegalic patients. The principal approaches to these objectives will include: a) Establishment of uniform criteria for the detection of GH secretory episodes (pulses); b) Indirect assessment of hypothalamic regulatory mechanisms of GH secretion via detailed estimation of the GH secretory patterns in normal versus acromegalic subjects; utilizing the aforementioned criteria; c) Establishment of the dose of exogenous GRF necessary to reproduce the spontaneous GH pulse amplitude in normal vs. acromegalic subjects; d) Examining the effects of the fasting- induced fall in somatomedin C generation upon the GH secretory pattern in patients with acromegaly; e) Administration of GRF to normal individuals and to patients with IGHD in a manner (dose/frequency) reproducing the endogenous GH secretion in patients with acromegaly; f) Studies of endogenous hypothalamic SRIF secretion. Normal adult men and women and patients with acromegaly or IGHD will participate in detailed protocols performed in the Clinical Research Center at the University of Michigan Hospital. Established radioimmunoassays will be used for serial hormone determinations. These studies will provide a more detailed understanding of the physiology of human GH secretion in normal and pathological conditions, and should allow new insights into the mechanisms of GH hypersecretion.
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